Cancer is a class of diseases in which a group of cells display uncontrolled growth, invasion and sometimes metastasis. Cancer affects people at all ages with the risk for most types increasing with age. Cancer causes about 13% of all human deaths.
Breast cancer is the leading cause of cancer in women and the second cause for women's mortality. Only 5-10% of the most abundantly occurring human breast cancers are familial breast cancers, induced by deficiencies and mutations of the tumor suppressor genes brca1 and brca2. All other human breast cancers are not induced by mutations of the tumor suppressor genes brca1 and brca2.
Tentori et al., Pharmacological research 52: 25-33 (2005) and Graziani et al. Pharmacological research 52: 109-118 (2005) review the use of several poly (ADP-ribose) polymerase (PARP) inhibitors (also named poly (ADP-ribose) synthetases and poly (ADP-ribose) transferases) in contributing to the treatment of cancer in combination with cytotoxic drugs.
Bryant et al., Nature 434, 913-917 (2005) and Farmer et al., Nature 434, 917-921 (2005) demonstrate that certain PARP inhibitors (such as AG14361) kill brca1 and brca2 deficient malignant cancer cells without affecting wild-type MCF-7 breast cancer cells. According to Bryant et al., supra, the sensitivity to the PARP inhibitor appears to be a direct consequence of the brca2 defect. Bryant et al., supra, further show that the survival of MCF7 cancer cells was reduced with PARP inhibitors only when brca2 was depleted from these cells.
In addition, De Soto et al., Int. J. Med. Sci, 3, 117-123 (2006) reviewed several papers showing, apart from the findings in Bryant et al., supra, and Farmer et al., supra, that CAPANI cells (which are deficient in brca2) were not inhibited by certain PARP inhibitors (such as NU1025), but were inhibited by other PARP inhibitors (such as KU0058684). Also, Bryant et al., supra, showed that only 50% MCF-7 brca1+/+ cells were eradicated by exposure for 10 consecutive days to the potent PARP inhibitor AG14361 (10 μM).
Pellicciari et al., (2003), Farmaco 58, 851 and Chiarugi et al. (2003), J. Pharmacol. Exp. Ther. 305, 943 describe the PARP-1 inhibitor Tiq-A (4H-thieno[2,3-c]isoquinolin-5-one) and its potential as neuroprotective agent.
M. Banasik, et al., J. Biol. Chem. 267, 1569 (1992) describe the PARP inhibitor Phen (6(5H)-phenanthridinone). D. Weltin, et al., Int. J. Immunopharmacol. 17, 265 (1995) describe immunological properties of Phen; D. Weltin, et al., Int. J. Radiat. Biol. 72, 685 (1997) describe the ability of Phen to increase radiation induced inhibition of cell proliferation. M. R. Cookson, et al, J. Neurochem. 70, 501 (1998) describe that Phen prevented cell death induced by hydrogen peroxide or peroxynitrite. D. S. Richardson, et al.; Adv. Exp. Med. Biol. 457, 267 (1999) describe that pretreatment with Phen and 3-aminobenzamide (3AB) in HL-60 myeloid leukemia cell lines resulted in resistance to apoptotic death rather than potentiation thereof.
F. Bernges & W. J. Zeller, J. Cancer Res. Clin. Oncol. 122, 665 (1996) describe that the PARP inhibitor 3-AB had no effect on the cytotoxicity of cisplatin.
WO 01/42219 discloses the PARP inhibitor PJ-34 (N-(6-oxo-5,6-dihydro-phenanthridin-2-yl)-N,N-dimethylacetamide, HCl) as a compound protecting against neuronal cell death induced by stroke or inflammation.
Tentori et al., supra, describes PJ-34 and its protective effects against cardiac dysfunction.
Pacher et al., (2002) J. Am. Coll. Cardiol. 40, 1006-1009 injected PJ-34 in rodents for a 10 week period to diminish cardiomyocytes cell death after cardiac stroke and to avoid chronic heart disease.
Cohen-Armon M. et al., (2007) Mol Cell 25, 297-308; Homburg et al., (2000) J. Cell Biol. 150:293-308; Visochek et al., (2005) J. Neurosci. 25:7420-742 describe that the survival of non-dividing cells, such as brain cortical neurons or cardiomyocytes is not affected following treatment with PJ-34.
Abdelkarim et al., (2001) Int. J. Mol. Med, 7, 255-260 and Park et al., (2004) Stroke, 35, 2896-2901 describe the neuroprotective effect of PJ-34 after stroke both in vivo and in vitro.
Inbar-Rozendal et al., (2009) Breast Cancer Research 11: R78 describe selective eradication of human nonhereditary breast cancer cells by phenanthridine-derived polyADP-ribose polymerase inhibitors.
Castiel A. et al., (2011) Cancer 11(1):412A discloses small molecule exclusively eradicates human cancer cells: Extra-centrosomes de-clustering agent BMC.
Castiel A. and Malka Cohen-Armon (2013) Journal of Visualized Experiments (JoVE) disclose cell death associated with abnormal mitosis observed by confocal imaging in live and fixed cancer cells.